2C (2C-x) is a general name for the family of psychedelic phenethylamines containing methoxy groups on the 2 and 5 positions of a benzene ring. Most of these compounds also carry lipophilic substituents at the 4 position, usually resulting in more potent and more metabolically stable and longer acting compounds.

Most of the early 2C drugs were developed by Alexander Shulgin in the 1970s and 1980s and were reviewed in his 1991 book PiHKAL (Phenethylamines I Have Known And Loved). 2C-B is the most popular of the 2C drugs. The prefix "2C" comes from the fact that they are phenethylamines rather than amphetamines and have two carbon atoms in their side chain, whereas the suffix (e.g.,the "–B" or "bromo" in the case of 2C–B) refers to the substituent at the 4-position.

Use and effects The 2C drugs are orally active at doses of 6to 150mg, depending on the drug, and have durations of 3to 48hours, also depending on the drug. Several have doses in the range of 10to 60mg and durations in the range of 4to 12hours. The 2C drugs produce psychedelic effects, such as perceptual enhancement, psychedelic visuals, and euphoria. Some, such as 2C-B, have also been reported to produce some entactogen-like effects, but findings in this area appear to be mixed.

+ Compound Chemical name Dose Duration 2C-AL 4-Allyl-2,5-dimethoxyphenethylamine Unknown Unknown 2C-B 4-Bromo-2,5-dimethoxyphenethylamine 10–35mg 4–8 hours 2C-Bu 4-Butyl-2,5-dimethoxyphenethylamine Unknown Unknown 2C-C 4-Chloro-2,5-dimethoxyphenethylamine 20–40mg 4–8 hours 2C-CN 4-Cyano-2,5-dimethoxyphenethylamine >22mg Unknown 2C-CP 4-Cyclopropyl-2,5-dimethoxyphenethylamine 15–35mg 3–6 hours 2C-D (2C-M) 4-Methyl-2,5-dimethoxyphenethylamine 20–60mg 4–6 hours 2C-E 4-Ethyl-2,5-dimethoxyphenethylamine 10–25mg 6–12 hours 2C-EF 4-Fluoroethyl-2,5-dimethoxyphenethylamine 6–20mg 8-12 hours 2C-F 4-Fluoro-2,5-dimethoxyphenethylamine ≥250mg Unknown 2C-G (2C-G-0) 3,4-Dimethyl-2,5-dimethoxyphenethylamine 20–35mg 18–30 hours 2C-G-3 3,4-Trimethylene-2,5-dimethoxyphenethylamine 16–25mg 12–24 hours 2C-G-5 3,4-Norbornyl-2,5-dimethoxyphenethylamine 10–16mg 32–48 hours 2C-G-N 1,4-Dimethoxynaphthyl-2-ethylamine 20–40 mg 20–30 hours 2C-H (2,5-DMPEA) 2,5-Dimethoxyphenethylamine Unknown Unknown 2C-I 4-Iodo-2,5-dimethoxyphenethylamine 14–22mg 6–10 hours 2C-iBu 4-Isobutyl-2,5-dimethoxyphenethylamine ≥5mg ~20 hours 2C-iP 4-Isopropyl-2,5-dimethoxyphenethylamine 8–25mg 8–12 hours 2C-N 4-Nitro-2,5-dimethoxyphenethylamine 100–150mg 4–6 hours 2C-O (2,4,5-TMPEA) 4-Methoxy-2,5-dimethoxyphenethylamine >300mg Unknown 2C-O-4 4-Isopropoxy-2,5-dimethoxyphenethylamine >60mg Unknown 2C-O-22 4-(2,2,2-Trifluoroethoxy)-2,5-dimethoxyphenethylamine ≥57mg Unknown 2C-P 4-Propyl-2,5-dimethoxyphenethylamine 6–10mg 5–16 hours 2C-Ph (2C-BI-1) 4-Phenyl-2,5-dimethoxyphenethylamine Unknown Unknown 2C-Se 4-Methylseleno-2,5-dimethoxyphenethylamine ~100mg 6–8 hours 2C-T (2C-T-1) 4-Methylthio-2,5-dimethoxyphenethylamine 60–100mg 3–5 hours 2C-T-2 4-Ethylthio-2,5-dimethoxyphenethylamine 12–25mg 6–8 hours 2C-T-3 (2C-T-20) 4-Methallylthio-2,5-dimethoxyphenethylamine 15–40mg 8–14 hours 2C-T-4 4-Isopropylthio-2,5-dimethoxyphenethylamine 8–20mg 12–18 hours 2C-T-7 4-Propylthio-2,5-dimethoxyphenethylamine 10–30mg 8–15 hours 2C-T-8 4-Cyclopropylmethylthio-2,5-dimethoxyphenethylamine 30–50mg 10–15 hours 2C-T-9 4-tert-Butylthio-2,5-dimethoxyphenethylamine 60–100mg 12–18 hours 2C-T-13 4-(2-Methoxyethylthio)-2,5-dimethoxyphenethylamine 25–40mg 6–8 hours 2C-T-15 4-Cyclopropylthio-2,5-dimethoxyphenethylamine >30mg Several hours 2C-T-16 4-Allylthio-2,5-dimethoxyphenethylamine 10–25mg 4–6 hours 2C-T-17 4-sec-Butylthio-2,5-dimethoxyphenethylamine 60–100mg 10–15 hours 2C-T-19 4-Butylthio-2,5-dimethoxyphenethylamine Unknown Unknown 2C-T-21 4-(2-Fluoroethylthio)-2,5-dimethoxyphenethylamine 8–20mg 7–10 hours 2C-T-21.5 4-(2,2-Difluoroethylthio)-2,5-dimethoxyphenethylamine 12–30mg 8–14 hours 2C-T-22 4-(2,2,2-Trifluoroethylthio)-2,5-dimethoxyphenethylamine >10mg ~6 hours 2C-T-25 4-Isobutylthio-2,5-dimethoxyphenethylamine >30mg Unknown 2C-T-27 4-Benzylthio-2,5-dimethoxyphenethylamine ≥80mg Unknown 2C-T-28 4-(3-Fluoropropylthio)-2,5-dimethoxyphenethylamine 8–20mg 8–10 hours 2C-T-30 4-(4-Fluorobutylthio)-2,5-dimethoxyphenethylamine >8mg Unknown 2C-T-33 4-(3-Methoxybenzylthio)-2,5-dimethoxyphenethylamine Unknown Unknown 2C-T-36 (2C-T-TFM) 4-Trifluoromethylthio-2,5-dimethoxyphenethylamine Unknown Unknown 2C-tBu 4-tert-Butyl-2,5-dimethoxyphenethylamine >5–10mg Unknown 2C-Te 4-Methyltelluro-2,5-dimethoxyphenethylamine Unknown Unknown 2C-TFE 4-(2,2,2-Trifluoroethyl)-2,5-dimethoxyphenethylamine 5–15mg 12–24 hours 2C-TFM 4-Trifluoromethyl-2,5-dimethoxyphenethylamine 3–6mg ≥5–10 hours 2C-V 4-Ethenyl-2,5-dimethoxyphenethylamine ~25mg ~5 hours 2C-YN 4-Ethynyl-2,5-dimethoxyphenethylamine ~50mg ~2 hours Refs:

Interactions

The 2C drugs are metabolized by the monoamine oxidase (MAO) enzymes, including both MAO-A and MAO-B. As a result, they may be potentiated by monoamine oxidase inhibitors (MAOIs), such as phenelzine, tranylcypromine, moclobemide, and selegiline. This may lead to overdose and serious toxicity. There are anecdotal reports of strong potentiation of 2C-B by MAOIs, including hospitalization. There is no known reversal agent for 2C drugs, and medical management for overdose involves treatment of symptoms until toxicity within the body subsides.

Pharmacology Pharmacodynamics Actions The 2C drugs act as agonists of the serotonin 5-HT2 receptors, including of the serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors. They are partial agonists of the serotonin 5-HT2A receptor. Most of the 2C drugs have much lower affinity for the serotonin 5-HT1A receptor than for the serotonin 5-HT2A receptor. Most of the 2C drugs have also shown about 5- to 15-fold higher affinity for the serotonin 5-HT2A receptor over the serotonin 5-HT2C receptor and about 15- to 100-fold higher affinity for the serotonin 5-HT2A receptor over the serotonin 5-HT1A receptor. The psychedelic effects of the 2C drugs are thought to be mediated specifically by activation of the serotonin 5-HT2A receptor.

Unlike many other phenethylamines, 2C drugs, including 2C-C, 2C-D, 2C-E, 2C-I, and 2C-T-2 among others, are inactive as monoamine releasing agents and reuptake inhibitors. Most of the 2C drugs are agonists of the rat and mouse trace amine-associated receptor 1 (TAAR1). However, most are inactive as agonists of the human TAAR1. The 2C drugs show very weak monoamine oxidase inhibition, including of monoamine oxidase A (MAO-A) and/or monoamine oxidase B (MAO-B).

+ Drug 5-HT1A 5-HT1B 5-HT2A 5-HT2B 5-HT2C Ki (nM) EC50 (nM) Emax (%) Ki (nM) Ki (nM) EC50 (nM) Emax (%) Ki (nM) EC50 (nM) Emax (%) Ki (nM) EC50 (nM) Emax (%) 2C-B 130–311 104.4 6.9–27.6 1.89–80 5–99% 13.5 75–130 52–89% 43–89.5 0.031–0.264 104–116% 2C-C 190–740 >10,000 <25% 252.9 5.47–13 9.27–200 49–102% 280 81% 5.4–90 24.2 94% 2C-D 440–1,630 >10,000 <25% 23.9–32.4 43.5–350 41–125% 230 77% 12.7–150 71.1 100% 2C-E 307.3–1,190 >10,000 <25% 4.50–43.9 2.5–110 40–125% 25.1 190 66% 5.4–104.1 0.233–18.0 98–106% 2C-H 70 1,600 2,408–9,400 28–67% 6,200 46% 4,100 2C-I 180–970 4,900 102% 3.5–9.3 3.83–60 15–82% 150 70% 10.2–40 2.8 79–100% 2C-N 2,200 23.5 170 20–48% 730 74% 370 40–50% 2C-P 110 8.1 90 63% 130 72% 40 2C-T-1 1,035 49 2.0 75% 57 58% 347 2C-T-2 370–1,740 3,000 76% 857.5 9–39.9 0.354–80 67–128% 6 130 75% 14.2–69 0.0233–3.8 87–107% 2C-T-4 470–916 27.9–54 5.5–220 56–87% 63–160 68–75% 180–295 2C-T-7 520–878 5.3–6.5 1.2–130 49–101% 52–350 45–75% 39–54 Notes: The smaller the value, the more avidly the drug binds to or activates the site. Refs:

Effects In accordance with their psychedelic effects in humans, the 2C drugs produce the head-twitch response and wet dog shakes, behavioral proxies of psychedelic effects, in rodents. At least some 2C drugs, such as 2C-D and 2C-E, produce hyperlocomotion at lower doses in rodents. All 2C drugs produce hypolocomotion at higher doses in rodents. 2C drugs, including 2C-C, 2C-D, 2C-E, and 2C-I, substitute partially to fully for psychedelics like DOM, DMT, and LSD and/or for the entactogen MDMA in rodent drug discrimination tests. However, none of the assessed 2C drugs substituted for dextromethamphetamine, suggesting that they lack amphetamine-type or stimulant-like effects.

In contrast to most psychedelics, at least two assessed 2C drugs, 2C-C and 2C-P, have shown reinforcing effects in rodents, including conditioned place preference (CPP) and self-administration. The mechanism by which these effects are mediated is unknown. However, it may be related to reduced expression of the dopamine transporter (DAT) and increased DAT phosphorylation, in turn resulting in increased extracellular dopamine levels in certain brain areas. These 2C drugs might have misuse potential in humans. Similar reinforcing effects in animals have been observed for NBOMe analogues of 2C drugs, including 25B-NBOMe, 25D-NBOMe, 25E-NBOMe, 25H-NBOMe, and 25N-NBOMe.

Similarly to DOI, tolerance has been found to gradually develop to the head-twitch response induced by 2C-T-7 with chronic administration in rodents.

Various 2C drugs show potent anti-inflammatory effects mediated by serotonin 5-HT2A receptor activation. Among these include 2C-I, 2C-B, 2C-H, and 2C-iBu. Others, such as 2C-B-Fly and 2C-T-33, were less effective. 2C-iBu has shown a greater separation between anti-inflammatory effects and psychedelic-like effects in animals than other 2C drugs and is being investigated for possible use as a pharmaceutical drug.

Pharmacokinetics The 2C drugs are orally active. They are metabolized by O-demethylation and deamination. This is mediated specifically by monoamine oxidase (MAO) enzymes MAO-A and MAO-B, whereas cytochrome P450 enzymes appear to metabolize only some 2C drugs and to have only a very small role.

Chemistry The 2C drugs, also known as 4-substituted 2,5-dimethoxyphenethylamines, are substituted phenethylamines and can be thought of as synthetic analogues of the naturally occurring phenethylamine psychedelic mescaline (3,4,5-trimethoxyphenethylamine). They are the phenethylamine (2C) analogues of the amphetamine (α-methylphenethylamine) DOx drugs like DOM, DOB, and DOI as well as of the phenylisobutylamine (α-ethylphenethylamine) 4C drugs like Ariadne (4C-D) and 4C-B. The N-benzylphenethylamines such as 25I-NBOMe, 25B-NBOMe, and 25C-NBOMe are derivatives of the 2C drugs. Certain FLY drugs such as 2C-B-FLY are also 2C derivatives.

Syntheses The chemical syntheses of 2C drugs have been described.

Analysis The chemical analysis of 2C drugs has been described.

History

2,4,5-Trimethoxyphenethylamine (2,4,5-TMPEA; 2C-O), the 2C positional isomer of mescaline (3,4,5-trimethoxyphenethylamine), was first synthesized by Max Jansen and was reported to produce psychedelic effects similar to those of mescaline in 1931. However, subsequent studies in the 1960s and 1970s suggested that 2,4,5-TMPEA may actually be inactive as a psychedelic in animals and humans.